This project defines how AIDS and cocaine use contribute to cardiac dysfunction. Sudden death and congestive heart failure as serious consequences of cocaine use. Cardiomyopathy (CM) has become an important complication of AIDS. Unfortunately, cocaine use and AIDS may coincide in the same patient. This suggests the possibility of additive or synergistic deleterious effects. The working hypothesis states: Cardiac dysfunction occurs in AIDS and in cocaine use. When AIDS and cocaine administration occur together, additive or synergistic effects worsen cardiac dysfunction, CM, and increase the risk of sudden death. Tumor necrosis factor alpha (TNFalpha) and endothelin-1 (ET-1) are expressed in both conditions. They exert changes in adrenergic responsiveness, calcium handling, and result in myocyte death and myocardial fibrosis. The AIMS of the project are: (1) to define altered cardiac performance and disturbed cardiac rhythm in AIDS and cocaine administration; (2) to define alterations in myocardial beta-adrenergic receptor (betaAR) density and subtype expression, expression of Ca transporters, and markers of remodeling in AIDS and cocaine administration; and (3) to define cardiac pathological features in AIDS and cocaine administration. A novel system of transgenic mice (TGs) that harbor replication- incompetent HIV-1 serves as an exquisite tool to help define pathophysiological events in AIDS with cocaine administration. TGs receive cocaine by constant infusion via osmotic minipumps. Preliminary data with this system indicate that cocaine is more cardiotoxic to AIDS TGs than to FVB/n wild types. It results in left ventricular hypertrophy (LVH), ventricular remodeling, decreased adrenergic responsiveness, ventricular expression of atrial natriuretic factor (ANF) and premature death. A multidisciplinary approach addresses pathophysiologic mechanisms. EKG telemetry identifies electrophysiological causes of sudden death from cocaine in AIDS. Serial echocardiographic measurements define ventricular performance, and chamber dimensions. Studies with isolated work-performing hearts identify contractile defects and control for load. BetaAR function studies biochemically define cardiac adrenergic receptor abundance and function. Abundance of mRNAs for elements of calcium handling and LV remodeling indicates cardiac molecular changes. Gross, light microscopic (LM) and ultrastructural (TEM) pathology studies pinpoint ventricular remodeling, myocyte death, and fibrosis and morphometrically quantitate these changes. Immuno-LM and immuno-TEM identify cellular and subcellular alterations.